PROJECT SUMMARY Mast cells function as innate sentinels, whose activation protects the host from infection but can also cause pathological inflammation. Therefore, new ways of intervening in mast cell function can benefit unmet clinical needs. A significant knowledge gap in immunology is the connection between inflammation and depression. These data are bi-directional: depression is common among patients with chronic inflammation; anti-inflammatory drugs can improve clinical depression; and anti-depressants have anti- inflammatory effects (1-8). These findings include an association between allergic disease and depression (9, 10). These links prompted us to examine effects of the commonly prescribed anti- depressants, selective serotonin reuptake inhibitors (SSRIs), on IgE-mediated mast cell function. We find that SSRIs suppress IgE- mediated mast cell degranulation and cytokine secretion in vitro and systemic anaphylactic shock in vivo. SSRI effects may be due to inhibiting purinergic receptors of the P2X family - ATP-gated ion channels expressed on neurons and many immune cells, including mast cells (11-17). ATP is rapidly released by IgE-activated mast cells (18), is elevated in inflamed tissues, and exacerbates inflammation by activating P2X receptors (19). Although the importance for P2X receptors in immune function is accepted, little is known about purinergic signaling in mast cells, how this is related to allergic disease, and any connection to SSRI therapy. We recently found that the suppressive effects of the SSRI fluoxetine are absent on mast cells lacking P2X3. Therefore, this project will test the hypothesis that SSRIs suppress IgE-mediated mast cell activation by inhibiting P2X3 function, preventing ATP-mediated exacerbation of allergic inflammation.